PROJECT SUMMARY/ABSTRACT Access to and demand for gender-affirming medical therapy for gender non-conforming youth have increased, but understanding of the ramifications of these therapies on bone development and skeletal health has lagged behind. Current guidelines recommend treatment of gender dysphoria as early as Tanner Stage 2 with gonadotropin-releasing hormone agonists for puberty suppression, but little is known about the skeletal effects of this intervention. Puberty is a key period of skeletal vulnerability, as rapid longitudinal bone growth coupled with a lag in mass accrual results in decreased bone strength and increased fracture incidence. Peak bone mass, achieved during puberty and young adulthood, largely determines age-related fractures in later life. One European group has demonstrated attenuation of bone mineral density (BMD) accrual after pubertal suppression in older transgender adolescents that did not recover despite subsequent gender-affirming hormone therapy. Major determinants of bone health such as body composition, vitamin D status, weight- bearing exercise, and dietary calcium intake were not assessed. The skeletal effects of puberty suppression in early pubertal transgender youth have never been reported. The objective of this fellowship proposal is to examine measures of bone mass and quality during pubertal suppression in early pubertal transgender youth and to correlate these bone measures with major determinants of bone health. Dr. Lee has designed the proposed longitudinal observational cohort study, during which she will collect and analyze anthropometric, laboratory, and imaging data. We hypothesize that BMD, bone microarchitecture, and bone strength estimates will have attenuated accrual in early pubertal transgender youth after one year of pubertal suppression when compared to puberty-matched, non-transgender, control youth. Dr. Lee's proposed research to test this this hypothesis will concurrently provide training in the use and interpretation of pediatric bone densitometry (Aim 1) and high-resolution peripheral quantitative computed tomography (Aim 2). She will additionally perform complex longitudinal data analyses to determine the relationships between major determinants of skeletal development and bone mass, microarchitecture, and strength (Aim 3). These results will inform current clinical practices and lead to longer-term studies and investigations of interventions to mitigate the expected lag in skeletal development during pubertal suppression. Ultimately, this research will positively contribute to the clinical care of transgender youth. Dr. Lee is training to become a physician-scientist at the intersection of bone metabolism and gender- affirming therapy, a highly relevant area in need of rigorous investigation. Her mentorship team is comprised of experts in endocrinology, radiology, epidemiology, and biostatistics. They will ensure that Dr. Lee fulfills her training goals in advanced skeletal imaging, complex longitudinal data analysis, and the endocrinology of bone and transgender care, which will bolster her application for career development award.